Page 440 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

418 PART IV Specific Malignancies in the Small Animal Patient

treatment. 25,31–35,113,117,118,136,140,141 The 1-, 2-, 3-, 4-, and 5-year of sarcoma development of at sites of vaccine administration has
survival probabilities are 80% to 94%, 72% to 87%, 61% to been estimated between 1 to 4/10,000 cases, 176,182,183 but as high
34,141
as 13 to 16/10,000 cases.
177,184,185
81%, 81%, and 76% respectively.
The ratio of ISSs to non-ISSs
VetBooks.ir invasiveness, surgical approach, completeness of excision, and has increased from 0.5 in 1989 to 4.3 in 1994. 186
Clinical factors associated with decreased ST include tumor
The time to tumor development postvaccination has been
local tumor recurrence, all of which may be related to some reported to be 4 weeks to 10 years, and is associated with a robust
degree. Dogs with grossly invasive and fixed STSs have a 5-fold inflammatory reaction around the tumor. 176 Adjuvant-con-
increased risk of tumor-related deaths, 25,34 presumably because taining vaccines have been proposed to be more likely to cause
of greater difficulty in achieving complete excision of their STSs. a vaccine site reaction and/or develop into an ISS 176 ; however,
Dogs treated with wide surgical resection have a MST of greater three large epidemiologic studies did not provide evidence that
than 1306 days compared with 264 days for dogs treated with aluminum-containing vaccines pose a greater risk, 175,178,187 and
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non–curative-intent surgeries. The MST for dogs with incom- thus it remains unclear whether nonadjuvanted vaccines are
pletely excised STSs is 657 days, and this is significantly worse safer. 180,187,188 A multicenter study of cats in the United States and
than the MST of greater than 1306 days for dogs with completely Canada found that no single vaccine manufacturer or vaccine type
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excised STSs. Dogs with local tumor recurrence have a 5-fold had a higher association with the development of ISSs. 178 Cats
risk of tumor-related death. 34 with pelvic limb ISSs are significantly more likely to have been
Histologic and IHC features associated with survival include vaccinated with an inactivated rabies vaccine than a recombinant
tumor necrosis, mitotic rate, histologic grade, argyrophilic nucle- rabies vaccine, and cats with interscapular ISSs were more likely to
olar organizer region (AgNOR) score, and Ki67 score. 31,34,35 have received long-acting corticosteroid injections. 187 Vaccination
Tumor-related deaths are three times more likely with greater than practices such as needle gauge, syringe reuse, use and shaking of
10% tumor necrosis and three times more likely with a mitotic multidose vials, mixing vaccines in a single syringe, and syringe
rate of 20 or more mitotic figures/10 HPFs. The MSTs for dogs type had no role in the development of tumors. 178
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with 10 or fewer, 10 to 19, and 20 or more mitotic figures/10 Although no vaccine type has been associated with a higher
HPFs are 1444 days, 532 days, and 236 days, respectively. His- risk of ISS development, nonadjuvanted vaccines are associ-
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tologic grade was prognostic in two adjuvant RT studies with an ated with less tissue inflammation compared with adjuvanted
MST not reached and greater than 1461 days for dogs with grade vaccines. 180 ISSs are hypothesized to develop from an inflam-
I and II STSs compared with 78 days for dogs with grade III STSs matory reaction induced by injectable medications that leads
in one study of incompletely excised STSs treated with fraction- to uncontrolled fibroblast and myofibroblast proliferation and
ated RT, 135 and a 940-day MST for dogs with grade III STSs eventual tumor formation, either alone or in association with
compared with an MST not reached for dogs with grade I and II immunologic factors. 189–193 The thought that inflammation
MSTs in dogs treated with incomplete excision and hypofraction- precedes tumor development is supported by histologic iden-
ated RT. 141 The MSTs and survival rates for dogs with STSs with tification of transition zones from inflammation to sarcoma
AgNORs below and above the median AgNOR scores were greater and microscopic foci of sarcoma located in areas of granulo-
than 1188 days and 76% versus greater than 1306 days and 53%, matous inflammation (Fig. 22.13). A similar phenomenon of
and dogs with an increased AgNOR score are 77 times more likely intraocular sarcoma development exists in cats after trauma or
to die as a result of their disease. Similarly, MSTs and survival chronic uveitis. 194–197 ISSs have also been reported to arise at
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rates for dogs with STSs with Ki67 scores below and above the sites of injections other than vaccines such as lufenuron, long-
median AgNOR scores were MST greater than 1188 days with acting steroids, nonsteroidal antiinflammatory drugs, cisplatin,
94% survival versus 657 days, and dogs with an increased Ki67 vascular access ports, deep nonabsorbable sutures, and micro-
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score are 12 times more likely to die as a result of their disease. chips, 187,198–204 and for this reason the term ISS is preferred to
vaccine-associated sarcoma.
Growth factors regulate the cellular events involved in granula-
Feline Sarcomas and Injection-Site Sarcomas tion tissue formation and wound healing. When these factors are
Epidemiology and Risk Factors added to fibroblast cultures, the cells develop a neoplastic pheno-
type. IHC identification and localization of growth factors and
The following events are linked to the development of postvac- their receptors are being investigated in ISSs. ISSs are immunoreac-
cinal sarcomas in the cat. The prevalence of feline rabies led to tive for platelet-derived growth factor (PDGF), epidermal growth
the enactment of a law in Pennsylvania in 1987 requiring rabies factor and its receptors, and transforming growth factor (TGF)-β.
vaccinations for cats. 171 In addition, two changes in vaccines Conversely, non–injection-site FSAs are negative or faintly posi-
occurred in the mid-1980s: development of a killed rabies vaccine tive for these factors and their receptors. 205,206 Lymphocytes in
licensed for subcutaneous administration and a killed vaccine for ISSs are positive for PDGF, but lymphocytes in non–injection-site
feline leukemia virus (FeLV). Epidemiologic studies have shown a FSAs and normal LNs are negative for PDGF. 205 Regional mac-
strong association between the administration of inactivated feline rophages also stain positively for PDGF receptor (PDGFR). Neo-
vaccines, such as rabies and FeLV, and subsequent development of plastic cells that are closest to lymphocytes in these tumors have
STSs at vaccination sites. 172–179 This is further supported by the the strongest staining for PDGFR, which has led to a hypothesis
significant decrease in interscapular injection-site sarcomas (ISSs) that lymphocytes in ISSs may secrete PDGF, recruit macrophages,
and significant increase in body wall and left and right pelvic limb and lead to fibroblast proliferation. 205,206 The expression of c-jun,
ISSs since the recommendations of the Vaccine-Associated Feline a proto-oncogene coding for the transcriptional protein AP-1, has
Sarcoma Task Force (VAFSTF) were published in 2001. 180,181 also been examined in ISSs. c-jun was found to be strongly posi-
Some authors report the reaction to vaccines was additive and this tive in ISSs and not expressed in non–injection-site FSAs. 205,206
increased the likelihood of sarcoma development with multiple FeLV and the feline sarcoma virus are not involved in the patho-
vaccines given at the same site simultaneously. 175 The prevalence genesis of feline ISSs. 207